Project Summary Alcohol associated health problems are a major medical burden in industrialized countries. Patients with alcoholic liver disease show intestinal bacterial dysbiosis and increased intestinal permeability. Disease severity correlates with systemic levels of translocated bacterial products. Although there is considerable progress in understanding the interaction between the host and intestinal bacteria, the role of the intestinal fungal microbiome (also called mycobiome) in alcoholic liver disease has not been investigated. Results from an international collaboration by Schnabl, Strkel and Fouts laboratories suggest that quantitative changes in the intestinal mycobiome and translocation of fungal products occur in a mouse model of alcoholic liver disease, while deep sequencing demonstrates intestinal fungal dysbiosis in patients with chronic alcohol abuse. Reducing intestinal fungal overgrowth with antifungals or restoring intestinal barrier function using probiotic Saccharomyces boulardii ameliorates experimental alcoholic liver disease. The central hypothesis of this proposed collaborative research application implicates disturbances in the intestinal mycobiome as an important etiological factor in the modulation of hepatic and systemic inflammation, and the development of alcoholic liver disease. We predict that chronic alcohol suppresses the intestinal immune system and facilitates qualitative and quantitative changes in the intestinal mycobiome. Fungal products such as ?-glucan translocate to the portal circulation and liver, and cause progression of alcoholic liver disease. Towards this goal, we will use pharmacological interventions, supplementation of probiotics and genetically modified mice in preclinical mouse models of alcoholic liver disease (Aim 1). We will characterize the intestinal mycobiome in patients with alcohol abuse, mild and progressive alcoholic liver disease. We predict that translocated fungal products correlate with levels of systemic and hepatic inflammation, and with the degree of liver disease (Aim 2). We believe these studies will provide important insights into alcohol-mediated changes of the intestinal mycobiome that result in fungal translocation. Eventually this approach might lead to new therapeutic targets for patients with alcoholic liver disease.